The physical discomfort associated with subcutaneous injection of insulin causes many type II diabetic patients to refuse insulin therapy entirely, while type I patients may refuse intensive treatment. A number of investigators have explored various alternative routes of administration of insulin in the hope of developing a substitute for injection.
Harrison and Cantab, "Insulin in Alcoholic Solution by Mouth", Br Med J, pp. 1204-1205 (1923), and Shichiri et al, "Increased Intestinal Absorption of Insulin in a Micellar Solution: water-in-oil-in-water insulin micelles", Acta Diabetol Lat, 15:175-183 (1978), examined the effect of delivering insulin enterically on blood glucose levels in humans and rabbits, respectively. Harrison et al. found that oral administration in alcohol would be too uncertain and too expensive to be of little therapeutic value in treating diabetics. Similarly, Shichiri et al. showed that the possibility of insulin absorption in a micellar form was impractical, since a reduction in blood glucose was only accomplished through intrajejunal administration and the required dose was 25-50 times that of an intramuscular dose.
Yamasaki et al, "The Effectiveness of Rectal Administration of Insulin Suppository in Normal and Diabetic Subjects", Diabetes Care. 4:454-458 (1981), tested the effectiveness of insulin administration by rectal suppository in normal and non-insulin-dependent non-obese diabetic subjects. They found that a dose 10 times the subcutaneous dose was necessary to lower blood glucose levels significantly, and some subjects complained of abdominal discomfort or a feeling of rectal urgency.
N. F. Fisher, "The Absorption of Insulin from the Intestine, Vagina, and Scrotal sac", Am J Physiol, 67:65-71 (1923), found that blood glucose levels in dogs were only temporarily reduced when insulin was administered through fistulae into the intestine or through vaginal administration. He found that scrotal administration of insulin resulted in a more sustained lowering of blood glucose in rabbits than with the other two routes of administration. However, this method of insulin delivery required injection into the scrotal sac and was not recommended for treatment of human diabetic patients.
Moses et al., "Insulin Administered Intranasally as an Insulin-bile salt Aerosol. Effectiveness and Reproducibility in Normal and Diabetic Subjects", Diabetes 32:1040-1047 (1983) reported that insulin administered intranasally as a bile-salt aerosol was effective in lowering blood glucose levels in diabetic subjects. Nevertheless, the amount of insulin absorbed through the nasal mucosa was approximately 10% of the dose delivered by intravenous injection and 2.5 times the subcutaneous dose was required to lower blood glucose. In addition, subjects reported nasal irritation and nasal congestion following administration, probably due to the presence of the bile acid.
Because of lower serum absorption and/or local irritation, none of these alternative routes of administration have been developed to replace insulin injection in the treatment of diabetes.
Creasia et al., "Efficacy of Inhaled Insulin: Effect of Adjuvant",FASEB J. 2: A537 (1988), and Almer et al. "Insulin Inhalation--at last a break-through", Diabetes Research and Clinical Practice, XIII Congress of the International Diabetes Federation: Sydney, Australia, S163 (1988), demonstrated that insulin aerosol delivered through the rat lung was effective in lowering serum glucose. Wigley et al., "Insulin Across Respiratory Mucosae by Aerosol Delivery", Diabetes, 20:552-556 (1971), and Elliott et al., "Parenteral Absorption of Insulin from the lung in Diabetic Children", Aust Paediatr J. 23:293-297 (1987), showed that insulin delivered to the human lung as an aerosol crosses the respiratory mucosa and retains biologic activity, since plasma insulin levels increased after insulin inhalation and blood glucose levels were lowered. Nevertheless, only one patient in the Wigley study achieved a normal blood glucose level following insulin inhalation, and none of the patients in the Elliott study responded with lowering of the blood glucose to within the normal range. The authors concluded that variable and inefficient absorption of insulin across the lung mucosa could account for their results. The dose of insulin available for inhalation at the mouth and the distribution of the available dose within the respiratory tract were not quantified in either study.
All U.S. patents and publications referred to herein are hereby incorporated by reference.